Despite societal trends for drug abuse to occur in adolescents and adults, men and women, basic research on drugs of abuse is seldom conducted with age and gender as independent variables. Despite findings that the psychostimulant, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), has neurobiological characteristics typical of drugs that alter the reinforcing efficacy of cocaine, the effects of MDMA on cocaine reinforcement have not been investigated. Thus, the overall aim of the present experiments is to examine the significance of age and gender in the long-term neurobehavioral effects of MDMA. The specific aims are as follows: 1) to record serotonin (5HT) and glutamate depletion in the brain of periadolescent and adult, male and female rats, exposed to MDMA; 2) to test the hypothesis that MDMA will increase the reinforcing effects; and 3) to examine neurotransmission following MDMA pre-exposure by recording behavioral responses to pretreatment with 5HT1B, 5HT2C or dopamine D1 receptor agonists before cocaine self- administration, and neurotransmitter levels in the nucleus accumbens and ventral tegmental area before and during cocaine self-administration. Together the proposed experiments will provide information on age and gender differences in 1) drug-related neurotoxicity and behavioral dysfunction; 2) the long-term effects 5HT dysfunction on the reinforcing properties of cocaine; and 3) the effects of 5HT neurotoxicity on monoaminergic interactions in the mesolimbic system. These investigations may provide insight into the etiology of stimulant dependence and may lead to novel pharmacotherapies for psychostimulant addiction.